Sjogren's syndrome, a systemic inflammatory autoimmune disease which occurs almost exclusively in females, is the leading cause of aqueous tear deficient dry eye. To date there is no cure for this disease and the precise mechanisms responsible for the decreased tear secretion are largely unknown. Studies from this laboratory point to a potentially pivotal role of the proinflammatory cytokines, interleukin-1alpha (IL-1a), IL-1beta (IL-lb), and tumor necrosis alpha (TNFa), in the impaired function of the lacrimal gland associated with Sjogren's syndrome. Specifically, we found that these cytokines have a dual target in the lacrimal gland: the nerve endings (i.e., inhibition of neurotransmitter release) and the epithelial cells (i.e., inhibition of lacrimal gland protein secretion). However, the mechanism(s) by which these cytokines interfere with lacrimal gland nerve endings and lacrimal gland acinar epithelial cell functions remain to be elucidated. Thus, the long term objective of the present proposal is to define the intracellular signaling pathways activated by proinflammatory stimuli to inhibit lacrimal gland secretion. A second objective is to test the effects of selective inhibitors of these pathways on lacrimal gland secretion using a murine model of Sjogren's syndrome. To obtain these goals, the following specific aims have been proposed: (1) define the signaling pathways activated by inflammatory stimuli to inhibit neurotransmitter release and lacrimal gland secretion; (2) determine if JNK, ERK, and iNOS are involved in the impaired lacrimal gland secretion associated with Sjogren's syndrome; and (3) determine if ICE activity is necessary for inflammation-induced inhibition of neurotransmitter release and lacrimal gland secretion. Lacrimal gland slices will be prepared from diseased and control female mice. Activation of JNK, ERK, and iNOS will be measured by western blotting. The release of neurotransmitter from lacrimal gland nerve endings and protein secretion will be measured spetrophotometrically. Selective inhibitors of JNK, ERK, and/or iNOS will be given subcutaneously to diseased and control female mice.